The ethicolegal framework relevant to human faecal microbiota transplants in South Africa: Part 3. Stool as a 'drug' or medicine.

The purpose of this article, the last in a series of three exploring the legal framework for the regulation of faecal microbiota transplantation (FMT) in South Africa (SA), is to determine the regulatory framework that applies to microbial-based treatments involving a level of manipulation that exceeds that of basic stool transplantation, e.g. processed FMT-derived products in capsule form. The article highlights the legal requirements for the registration of these products as biological medicines in SA law. Although human stool banks are not regulated in terms of the National Health Act 61 of 2003 (NHA) and regulations, the earlier articles point out that human stool fits the definition of human tissue and human biological material as defined by the NHA. For this reason, stool banks should be considered tissue banks in terms of the NHA and regulations. Healthcare practitioners and researchers involved in FMT banking and transplantation should strive to comply with these regulations in the absence of clear legal direction at present.

The ethicolegal framework relevant to human faecal microbiota transplants in South Africa: Part 2. Human stool as tissue?

Faecal microbiota transplantation (FMT) has been shown to be an effective treatment for recurrent Clostridioides difficile infection. The purpose of this article, the second of a series of three articles, is to explore the legal framework governing human FMT in South Africa (SA). FMT involves different modes of administration that require different regulatory considerations. The focus of this article is to explore the legal classification of human stool as tissue in terms of the National Health Act 61 of 2003, as well as the regulation of human stool banks as tissue banks. The article concludes with specific recommendations aimed at improving the current regulatory vacuum relating to the regulation of FMT in SA.

Low-risk trials for children and pregnant women threatened by unnecessary strict regulations. Does the coming EU Clinical Trial Regulation offer a solution?

Investigator-initiated clinical trials are crucial for improving quality of care for children and pregnant women as they are often excluded from industry-initiated trials. However, trials have become increasingly time-consuming and costly since the EU Clinical Trial Directive entered into force in 2001. This directive made compliance with ICH-Good Clinical Practice Guidelines (ethical and quality standard for conducting human subject research) mandatory for all clinical trials, regardless of its risk-classification. By discussing two investigator-initiated, 'low-risk' drug trials, we aim to illustrate that compliance with all GCP requirements makes trials very laborious and expensive, while a clear rationale is missing. This discourages clinical researchers to start and carry out investigator-initiated research. However, the forthcoming EU Clinical Trial Regulation (No 536/2014) seems to provide a solution as it allows for less stringent rules for low-risk trials. We want to raise awareness for these developments in both the clinical research community and the European and national regulatory authorities. Implementation of this forthcoming Regulation regulatory policies should be done in such a way that investigator-initiated trials evaluating standard care interventions will become more feasible. This will allow us to obtain evidence on optimal and safe treatments, especially for groups that are underrepresented in medical research. What is Known • Investigator-initiated trials are indispensable for improving care for children and pregnant women as they are often excluded from industry-initiated trials • Trials have become increasingly time-consuming and costly because of mandatory compliance with ICH-GCP guidelines What is New • The forthcoming EU Clinical Trial Regulation allows less stringent rules for low-risk trials • The national legislator and regulatory authorities should recognize the importance of this opportunity and implement the Regulation in such a way that investigator-initiated trials will become more feasible.

Typhoidal Salmonella human challenge studies: ethical and practical challenges and considerations for low-resource settings.

Typhoidal Salmonella is a major global problem affecting more than 12 million people annually. Controlled human infection models (CHIMs) in high-resource settings have had an important role in accelerating the development of conjugate vaccines against Salmonella Typhi.The typhoidal Salmonella model has an established safety profile in over 2000 volunteers in high-income settings, and trial protocols, with modification, could be readily transferred to new study sites. To date, a typhoidal Salmonella CHIM has not been conducted in a low-resource setting, although it is being considered.Our article describes the challenges posed by a typhoidal Salmonella CHIM in the high-resource setting of Oxford and explores considerations for an endemic setting.Development of CHIMs in endemic settings is scientifically justifiable as it remains unclear whether findings from challenge studies performed in high-resource non-endemic settings can be extrapolated to endemic settings, where the burden of invasive Salmonella is highest. Volunteers are likely to differ across a range of important variables such as previous Salmonella exposure, diet, intestinal microbiota, and genetic profile. CHIMs in endemic settings arguably are ethically justifiable as affected communities are more likely to gain benefit from the study. Local training and research capacity may be bolstered.Safety was of primary importance in the Oxford model. Risk of harm to the individual was mitigated by careful inclusion and exclusion criteria; close monitoring with online diary and daily visits; 24/7 on-call staffing; and access to appropriate hospital facilities with capacity for in-patient admission. Risk of harm to the community was mitigated by exclusion of participants with contact with vulnerable persons; stringent hygiene and sanitation precautions; and demonstration of clearance of Salmonella infection from stool following antibiotic treatment.Safety measures should be more stringent in settings where health systems, transport networks, and sanitation are less robust.We compare the following issues between high- and low-resource settings: scientific justification, risk of harm to the individual and community, benefits to the individual and community, participant understanding, compensation, and regulatory requirements.We conclude that, with careful consideration of country-specific ethical and practical issues, a typhoidal Salmonella CHIM in an endemic setting is possible.

Ethics of alternative trial designs and methods in low-resource settings.

This editorial introduces articles in this Special Issue, which are based on presentations given at the 2017 meeting of the Global Forum of Bioethics in Research meeting. The main themes presented at the meeting were the use of cluster randomized trials, stepped-wedge cluster randomized trials, and controlled human infection models in research conducted in low-resource settings. The editorial sets out which ethical issues may arise in the context of alternative trial designs and describes the articles in this issue that addresses some or more of the ethical issues, such as justification of the research design, risk-benefit evaluations and consent.

Regulating impact on bystanders in clinical trials: An unsettled frontier.

This article informally reviews key research ethics guidelines and regulations, academic scholarship, and research studies and finds wide variety in how they consider risk to bystanders in medical research (namely, non-participants whom studies nevertheless place at risk). Some of these key sources give no or very little consideration to bystanders, while others offer them the utmost protection (greater than they offer study participants). This unsettled frontier would benefit from a deeper investigation of the ethics of protecting research bystanders.

Regulatory aspects of prospective and retrospective clinical research in France in 2018.

In France, the so-called "Jardé law" (named for its proposer) on human research, implemented since 2016, defines the regulatory and legal framework for "prospective" studies, formerly known as "biomedical research" or "common care". Three categories are distinguished: type 1 is at-risk drug or non-drug interventional research, type 2 is low-risk, low-burden interventional research, and type 3 is non-interventional research. The decrees of April 12, 2018 precisely define a list of research categories for types 2 and 3, thereby clarifying the regulatory procedures. The Sponsor registers the trial on the database of the National Drug Safety Agency (ANSM), or the European EudraCT database for drug studies, to obtain an identification number. Regulatory procedures are undertaken with the IRB and ANSM and then the Data Protection Commission (CNIL). Retrospective research on previously collected data (other than genetic) does not come under the Jardé law, and is governed by the 1978 data protection law, updated by the application decree of December 2016 and the law No. 2018-493 of June 20, 2018 on protection of personal data. This article presents a clarification of the key methodologic and regulatory steps.

An Industry Perspective on the 2017 EMA Guideline on First-in-Human and Early Clinical Trials.

The European Medicines Agency (EMA) in 2017 issued a revised guideline on nonclinical and clinical aspects of first-in-human (FIH) and early clinical trials (CTs). External input was solicited during a draft comment phase, and although some industry suggestions were adopted, others were not. We agree that subject safety is of utmost priority, and believe that minimizing risk must be balanced with efficient and informative study designs to bring new medicines to patients.

Promoting Safe Early Clinical Research of Novel Drug Candidates: A European Union Regulatory Perspective.

The European Medicines Agency (EMA) revises its guideline on minimizing risk in first-in-human trials to reflect changing practice and in light of a recent tragic incident.

Paying Research Participants: Regulatory Uncertainty, Conceptual Confusion, and a Path Forward.

The practice of offering payment to individuals in exchange for their participation in clinical research is widespread and longstanding. Nevertheless, such payment remains the source of substantial debate, in particular about whether or the extent to which offers of payment coerce and/or unduly induce individuals to participate. Yet, the various laws, regulations, and ethical guidelines that govern the conduct of human subjects research offer relatively little in the way of specific guidance regarding what makes a payment offer ethically acceptable-or not. Moreover, there is a lack of definitional agreement regarding what the terms coercion and undue inducement mean in the human subjects research context. It is, therefore, unsurprising that investigators and Institutional Review Boards (IRBs) experience confusion about how to evaluate offers of payment, and lean toward conservative approaches. These trends are exemplified by our pilot data regarding the ways in which some IRB members and investigators (mis)understand the concepts of coercion and undue inducement, as well as the ways in which certain research institutions oversee offers of payment at a local level. This article systematically examines the legal and ethical dimensions of offering payment to research participants. It argues that many concerns about offers of payment to research participants can be attributed to the misguided view that such offers ought to be treated differently than offers of payment in other contexts, a form of "research exceptionalism." We show that rejection of research exceptionalism with respect to payment helps settle open debates about both how best to define coercion and undue influence, and how to understand the relation between these concepts and offers of payment. We argue for adoption of our preferred definitions, ideally by regulatory authorities, and against the conventional conservatism toward payment of research participants. Instead, we draw attention to the rarely asked, even radical, question: are research participants paid enough? We conclude by arguing that we ought to change the default to favor, rather than encourage suspicion of, offers of payment to research participants.

Principales implicaciones del nuevo Real Decreto de ensayos clínicos para los urgenciólogos investigadores / New Royal Decree on clinical trials: main implications for emergency medicine physicians who do research

La puesta en marcha de una nueva regulación europea para la realización de ensayos clínicos con medicamentos ha supuesto cambios importantes en España, que se han traducido en la publicación de un Real Decreto que regula la realización de ensayos clínicos y que entró en vigor en enero de 2016. El nuevo Real Decreto pretende sentar las bases para trabajar de acuerdo con la normativa europea, regula los comités de ética de investigación con medicamentos (CEIm) que deben evaluar los estudios, introduce medidas para facilitar la investigación clínica y clarifica el Registro Español de Estudios Clínicos, entre otras cosas. Se revisan las modificaciones más importantes, sobre todo las que van dirigidas a facilitar la investigación, como las nuevas figuras que se crean de «Ensayo clínico de bajo nivel de intervención» e «Investigación clínica sin ánimo comercial». Estas figuras pueden resultar especialmente positivas para la realización de ensayos clínicos por parte de los urgenciólogos. También se comentan los cambios que se establecen para la investigación en poblaciones vulnerables y las modificaciones en la documentación que hay que presentar tanto al CEIm como a la Agencia Española de Medicamentos y Productos Sanitarios (AU)

The new European Union directives affecting clinical trials of medicines introduced important changes for Spain, leading to the publication of a Royal Decree regulating the conduct of clinical trials that went into effect in January 2016. The decree sets out the principles for complying with the EU directives, regulates the work of institutional review boards (IRBs) or ethics committees that review research proposals, introduces means to facilitate clinical research, and clarifies the role of the Spanish register of clinical trials, among other topics. This paper discusses the main changes that have been introduced, especially those intended to facilitate research, such as the new concepts of low intervention trial and noncommercial clinical research. These concepts may be particularly useful for clinical trials designed by emergency medicine physicians. We also comment on changes affecting vulnerable populations and the documents that must be presented to both the researchers’ IRB and the Spanish Agency for Medicines and Health Care Products (AU)

Guardianship and Clinical Research Participation: The Case of Wards with Disorders of Consciousness.

We review relevant federal law about research on human subjects and state laws on guardian authority to determine whether guardians can consent on behalf of their wards to participation in research. The Common Rule is silent on the issue as are most state guardianship laws. Our analysis shows significant variation in guardians' decision-making authority in the states that do regulate wards' participation in research.We consider how the appointment of guardians for patients with disorders of consciousness (DOC) impacts such patients' access to research. We assert that it is important that such persons be permitted to participate in research, so that their conditions and potential medical interventions can be studied, and that those with similar conditions can benefit from the knowledge gained from these studies. We argue that state guardianship laws should be adapted to specifically give guardians the authority to consent to research on behalf of wards who may be able to regain decisional capacity.

[Informed consent for clinical investigation in the critically ill patient. An introduction to the regulation 536/2014/EC on clinical investigation of medicinal products for human use, repealing Directive 2001/20/EC]. / Il consenso informato alla sperimentazione clinica nel paziente critico.Introduzione al Regolamento UE n. 536/2014 sulla sperimentazione clinica di medicinali per uso umano che abroga la Direttiva 2001/20/CE.

The principle of patient information, awareness and documented consent for the participation in clinical trials is a cornerstone in the modern ethics of clinical research. However, this procedure is seldom applicable in the critically ill patient who becomes suddenly incapable of fully evaluating the risk vs benefit of the alternative therapeutic options. This issue becomes particularly problematic in those conditions where the benefit of any intervention is highly time-dependent, such as acute myocardial infarction, stroke, cardiac arrest, polytrauma and other similar conditions. The new directive 536/2014/EC defines the concept that in these cases the expert clinician and the Ethics Committees, based upon a rigorous study protocol, are in better conditions, as compared to patients' proxies and any legal representative, to take an appropriate decision. This decision should be later confirmed (deferred consent) by the patient, in case he returns competent, or by his proxies or legal tutor, in order to use experimental data. The new directive ends a long period of disparity among the Member States, some of which had taken unilateral decisions allowing the participation of incapable patients, whereas others, among which Italy, had a more conservative approach. Unfortunately, owing to technical and bureaucratic issues, the new regulation is unlikely to become active before the beginning of 2018.

A Framework for Conducting Deceased Donor Research in the United States.

There are a number of regulatory barriers both perceived and real that have hampered widespread clinical research in the field of donation and transplantation. This article sets forth a framework clarifying the existing legal requirements and their application to the conduct of research on deceased donors and donor organs within the United States. Recommendations are focused on resolving some of the ambiguity surrounding deceased donor authorization for research, Health Insurance Portability and Accountability Act requirements and the role of institutional review board oversight. The successful conduct of clinical research in the field of donation and transplantation requires an understanding of these regulatory nuances as well as identification of important ethical principles to consider. Facilitation of these concepts will ultimately provide support for innovative research designed to increase the availability of organs for transplantation. Further work identifying the optimal infrastructure for overview of clinical research in the field should be given priority.

Shared vulnerabilities in research.

The U.S. Code of Federal Regulations governing federally funded research on human subjects assumes that harmful research is sometimes morally justifiable because the beneficiaries of that research share a particular vulnerability with its subjects. In this article, I argue against this assumption, which occurs in every subpart of the Code of Federal Regulations that deals with specific vulnerable populations (pregnant women, fetuses, neonates, prisoners, and children). I argue that shared vulnerability is no exception to the general principle that harming one person in order to benefit another is no more justifiable if the two people have traits in common. Further, shared vulnerability is not a reasonable proxy for any morally relevant desideratum of research, in particular the desire to benefit the worst off, the desire to avoid exploitation, and the desire to use vulnerable populations in research only when necessary.

Helsinki 50 years on.

Ever since its adoption the Declaration of Helsinki has been universally recognised as a key landmark in the ethics of medical research involving human subjects. Over fifty years it has been revised seven times and supplemented twice with explanatory notes. The debate surrounding its contents and organisation continues unabated and becomes particularly lively every time the text is reviewed. One of the most controversial issues is recourse to the placebo: the conditions laid down for its use are held by many to offer insufficient guarantees for the protection of those receiving it.